Abstract:
:The enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a2-adrenoceptor, which complicates the interpretation of their pharmacology. A bisubstrate analogue approach offers the potential for development of highly selective inhibitors of PNMT. This paper documents the design, synthesis, and evaluation of such analogues, several of which were found to possess human PNMT (hPNMT) inhibitory potency <5 nM versus AdoMet. Site-directed mutagenesis studies were consistent with bisubstrate binding. Two of these compounds (19 and 29) were co-crystallized with hPNMT and the resulting structures revealed both compounds bound as predicted, simultaneously occupying both substrate binding domains. This bisubstrate inhibitor approach has resulted in one of the most potent (20) and selective (vs the a2-adrenoceptor) inhibitors of hPNMT yet reported.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lu J,Bart AG,Wu Q,Criscione KR,McLeish MJ,Scott EE,Grunewald GLdoi
10.1021/acs.jmedchem.0c01475subject
Has Abstractpub_date
2020-11-25 00:00:00pages
13878-13898issue
22eissn
0022-2623issn
1520-4804journal_volume
63pub_type
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